Abstract

First described in 1983, Barth syndrome (BTHS) is widely regarded as a rare X-linked
genetic disease characterised by cardiomyopathy (CM), skeletal myopathy, growth delay,
neutropenia and increased urinary excretion of 3-methylglutaconic acid (3-MGCA). Fewer
than 200 living males are known worldwide, but evidence is accumulating that the disorder
is substantially under-diagnosed. Clinical features include variable combinations
of the following wide spectrum: dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy
(HCM), endocardial fibroelastosis (EFE), left ventricular non-compaction (LVNC), ventricular
arrhythmia, sudden cardiac death, prolonged QTc interval, delayed motor milestones,
proximal myopathy, lethargy and fatigue, neutropenia (absent to severe; persistent,
intermittent or perfectly cyclical), compensatory monocytosis, recurrent bacterial
infection, hypoglycaemia, lactic acidosis, growth and pubertal delay, feeding problems,
failure to thrive, episodic diarrhoea, characteristic facies, and X-linked family
history. Historically regarded as a cardiac disease, BTHS is now considered a multi-system
disorder which may be first seen by many different specialists or generalists. Phenotypic
breadth and variability present a major challenge to the diagnostician: some children
with BTHS have never been neutropenic, whereas others lack increased 3-MGCA and a
minority has occult or absent CM. Furthermore, BTHS was first described in 2010 as
an unrecognised cause of fetal death. Disabling mutations or deletions of the tafazzin (TAZ) gene, located at Xq28, cause the disorder by reducing remodeling of cardiolipin,
a principal phospholipid of the inner mitochondrial membrane. A definitive biochemical
test, based on detecting abnormal ratios of different cardiolipin species, was first
described in 2008. Key areas of differential diagnosis include metabolic and viral
cardiomyopathies, mitochondrial diseases, and many causes of neutropenia and recurrent
male miscarriage and stillbirth. Cardiolipin testing and TAZ sequencing now provide relatively rapid diagnostic testing, both prospectively and
retrospectively, from a range of fresh or stored tissues, blood or neonatal bloodspots.
TAZ sequencing also allows female carrier detection and antenatal screening. Management
of BTHS includes medical therapy of CM, cardiac transplantation (in 14% of patients),
antibiotic prophylaxis and granulocyte colony-stimulating factor (G-CSF) therapy.
Multidisciplinary teams/clinics are essential for minimising hospital attendances
and allowing many more individuals with BTHS to live into adulthood.